Inhibitor of DNA-binding protein

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Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of proteins that heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins. [1] ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding domain and thus regulate bHLH transcription factors when they heterodimerize with bHLH proteins. [2] The first helix-loop-helix proteins identified were named E-proteins because they bind to Ephrussi-box (E-box) sequences. [3] In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive. [1] E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription. [4] Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in Drosophila is called extramacrochaetae (EMC) and encodes a transcription factor of the helix-loop-helix family that lacks a DNA binding domain. EMC regulates cell proliferation, formation of organs like the midgut, and wing development. [5] ID proteins could be potential targets for systemic cancer therapies without inhibiting the functioning of most normal cells because they are highly expressed in embryonic stem cells, but not in differentiated adult cells. [6] Evidence suggests that ID proteins are overexpressed in many types of cancer. For example, ID1 is overexpressed in pancreatic, breast, and prostate cancers. ID2 is upregulated in neuroblastoma, Ewing’s sarcoma, and squamous cell carcinoma of the head and neck. [6]

Contents

Function

ID proteins are key regulators of development where they function to prevent premature differentiation of stem cells. [7] By inhibiting the formation of E-protein dimers that promote differentiation, ID proteins can regulate the timing of differentiation of stem cells during development. [8] An increase in ID expression is seen in embryonic and adult stem cells. ID proteins also promote cell cycle progression, delaying senescence, and help facilitate cell migration. [9] In contrast, inappropriate regulation of ID proteins in differentiated cells can contribute to tumorigenesis. [10] [11] [12] Generally, IDs function as oncogenes. When ID proteins are overexpressed, cell proliferation is enhanced and cells become insensitive to growth factor depletion. [11] Expression of ID proteins in neurons halts neuron axon growth and allows elongation of neurons. [13] Knockout mouse data show that ID genes are essential for heart development. [14] There is some controversy surrounding the ID proteins and their role in cancer, but overexpression is seen in most tumor types. [8] There are a few exceptions, for example, an increase in ID1 expression in brain cancer is correlated with a better prognosis, while a decrease in ID4 expression in colon and rectal cancers is linked to a poorer prognosis. [8] ID proteins can bind E-proteins, preventing them from binding bHLH proteins and halting transcription, a case often seen in cancerous phenotypes. [1]

Subtypes

Humans express four types of Id proteins (called ID1, ID2, ID3, and ID4).

A recent publication in Cancer Research (August 2010) has shown that ID1 can be used to mark endothelial progenitor cells which are critical to tumour growth and angiogenesis. This publication has demonstrated that targeting ID1 resulted in decreased tumour growth. Therefore, ID1 could be used to design a novel cancer therapy. [15]

Perk, Iavarone, and Benezra, (2005), reviewed fifteen studies and compiled a list of the phenotypic effects of each ID gene when knocked out in mice. [1] When ID1 was knocked out, a defect in T-cell migration was seen. A knockout of ID2 showed that 25% of mice died perinatally, and those born lacked lymph nodes and showed defects in mammary proliferation. Generally, normal development was seen in mice with an ID3 knockout, but they did have a defect in B-cell proliferation. Neural defects and premature differentiation were seen in mice lacking ID4. Knockout of both ID1 and ID3 resulted in embryonic lethality due to brain hemorrhages and abnormalities in cardiac development. [1]

Related Research Articles

Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.

The scleraxis protein is a member of the basic helix-loop-helix (bHLH) superfamily of transcription factors. Currently two genes have been identified to code for identical scleraxis proteins.

The gene extramachrochaetae (emc) is a Drosophila melanogaster gene that codes for the Emc protein, which has a wide variety of developmental roles. It was named, as is common for Drosophila genes, after the phenotypic change caused by a mutation in the gene.

MYC

MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene which is a member of the myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.

ETS1

Protein C-ets-1 is a protein that in humans is encoded by the ETS1 gene. The protein encoded by this gene belongs to the ETS family of transcription factors.

ID2 Protein-coding gene in the species Homo sapiens

DNA-binding protein inhibitor ID-2 is a protein that in humans is encoded by the ID2 gene.

FLI1

Friend leukemia integration 1 transcription factor (FLI1), also known as transcription factor ERGB, is a protein that in humans is encoded by the FLI1 gene, which is a proto-oncogene.

LMO2

LIM domain only 2, also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the LMO2 gene.

ID1

DNA-binding protein inhibitor ID-1 is a protein that in humans is encoded by the ID1 gene.

USF1

Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.

MAX (gene)

MAX is a gene that in humans encodes the MAX transcription factor.

ID3 (gene)

DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.

TFE3

Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.

HES1

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

ASCL1

Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.

ID4 Protein-coding gene in humans

ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.

LYL1

Protein lyl-1 is a protein that in humans is encoded by the LYL1 gene.

Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

ASCL2

Achaete-scute complex homolog 2 (Drosophila), also known as ASCL2, is an imprinted human gene.

ETS transcription factor family

In the field of molecular biology, the ETSfamily is one of the largest families of transcription factors and is unique to animals. There are 29 genes in humans, 28 in the mouse, 10 in Caenorhabditis elegans and 9 in Drosophila. The founding member of this family was identified as a gene transduced by the leukemia virus, E26. The members of the family have been implicated in the development of different tissues as well as cancer progression.

References

  1. 1 2 3 4 5 Perk J, Iavarone A, Benezra R (August 2005). "Id family of helix-loop-helix proteins in cancer". Nature Reviews. Cancer. 5 (8): 603–14. doi:10.1038/nrc1673. PMID   16034366. S2CID   19850793.
  2. ↑ Pagliuca A, Bartoli PC, Saccone S, Della Valle G, Lania L (May 1995). "Molecular cloning of ID4, a novel dominant negative helix-loop-helix human gene on chromosome 6p21.3-p22". Genomics. 27 (1): 200–3. doi:10.1006/geno.1995.1026. PMID   7665172.
  3. ↑ Wang LH, Baker NE (2015). "E Proteins and ID Proteins: Helix-Loop-Helix Partners in Development and Disease". Dev Cell. 35 (3): 269–80. doi:10.1016/j.devcel.2015.10.019. PMC   4684411 . PMID   26555048.
  4. ↑ Kondo M, Cubillo E, Tobiume K, Shirakihara T, Fukuda N, Suzuki H, Shimizu K, Takehara K, Cano A, Saitoh M, Miyazono K (October 2004). "A role for Id in the regulation of TGF-beta-induced epithelial-mesenchymal transdifferentiation". Cell Death and Differentiation. 11 (10): 1092–101. doi: 10.1038/sj.cdd.4401467 . PMID   15181457.
  5. ↑ Brody T B (1998). "The interactive fly: Extra macrochaetae".
  6. 1 2 Fong S, Debs RJ, Desprez PY (August 2004). "Id genes and proteins as promising targets in cancer therapy". Trends in Molecular Medicine. 10 (8): 387–92. doi:10.1016/j.molmed.2004.06.008. PMID   15310459.
  7. ↑ Yokota Y (December 2001). "Id and development". Oncogene. 20 (58): 8290–8. doi: 10.1038/sj.onc.1205090 . PMID   11840321.
  8. 1 2 3 Lasorella A, Benezra R, Iavarone A (February 2014). "The ID proteins: master regulators of cancer stem cells and tumour aggressiveness". Nature Reviews. Cancer. 14 (2): 77–91. doi:10.1038/nrc3638. PMID   24442143. S2CID   31055227.
  9. ↑ Ling F, Kang B, Sun XH (2014). "Id proteins: small molecules, mighty regulators". Current Topics in Developmental Biology. 110: 189–216. doi:10.1016/B978-0-12-405943-6.00005-1. PMID   25248477.
  10. ↑ Benezra R, Rafii S, Lyden D (December 2001). "The Id proteins and angiogenesis". Oncogene. 20 (58): 8334–41. doi: 10.1038/sj.onc.1205160 . PMID   11840326. S2CID   7533233.
  11. 1 2 Lasorella A, Uo T, Iavarone A (December 2001). "Id proteins at the cross-road of development and cancer". Oncogene. 20 (58): 8326–33. doi: 10.1038/sj.onc.1205093 . PMID   11840325.
  12. ↑ Zebedee Z, Hara E (December 2001). "Id proteins in cell cycle control and cellular senescence". Oncogene. 20 (58): 8317–25. doi: 10.1038/sj.onc.1205092 . PMID   11840324.
  13. ↑ Iavarone A, Lasorella A (December 2006). "ID proteins as targets in cancer and tools in neurobiology". Trends in Molecular Medicine. 12 (12): 588–94. doi:10.1016/j.molmed.2006.10.007. PMID   17071138.
  14. ↑ Cunningham TJ, Yu MS, McKeithan WL, Spiering S, Carrette F, Huang CT, et al. (July 2017). "Id genes are essential for early heart formation". Genes & Development. 31 (13): 1325–1338. doi: 10.1101/gad.300400.117 . PMC   5580654 . PMID   28794185.
  15. ↑ Mellick AS, Plummer PN, Nolan DJ, Gao D, Bambino K, Hahn M, Catena R, Turner V, McDonnell K, Benezra R, Brink R, Swarbrick A, Mittal V (September 2010). "Using the transcription factor inhibitor of DNA binding 1 to selectively target endothelial progenitor cells offers novel strategies to inhibit tumor angiogenesis and growth". Cancer Research. 70 (18): 7273–82. doi:10.1158/0008-5472.CAN-10-1142. PMC   3058751 . PMID   20807818.
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